In the pathological state of osteoarthrosis, degradation of the aggrecan, the main proteoglycan of articular cartilage, represents a very early and crucial event. The pathological loss of the cartilage aggrecan results from proteolytic cleavages in its interglobular domain. Amino acid sequence analyses of proteoglycan metabolites isolated from the synovial fluid of patients suffering from joint damage, osteoarthrosis or an inflammatory joint disorder have shown that a proteolytic cleavage takes place preferentially between the amino acids Glu373 and Ala374 in the interglobular domain of human aggrecan (Lohmander et al., Arthritis Rheum. 36, (1993), 1214-1222). The proteolytic activity responsible for this cleavage is referred to as “aggrecanase” and may be assigned to the superfamily of metalloproteinases (MP).
Zinc is essential in the catalytically active site of metalloproteinases. MPs cleave collagen, laminin, proteoglycans, elastin or gelatin under physiological conditions and therefore play an important role in bone and connective tissue. A large number of different MP inhibitors are known (J. S. Skotnicki et al., Ann. N.Y. Acad. Sci. 878, 61-72 (1999); EP 0 606 046; WO94/28889). Some of these inhibitors are not well characterized in relation to their specificity; others are more or less selectively directed in particular against matrix metalloproteinases (MMPs).
Aggrecanase differs from matrix metalloproteinases (MMPs) by its different specificity, which is directed against particular cleavage sites which occur in aggrecan and are not favored by MMPs. The cleavage results in characteristic fragments which can be detected by using suitable antibodies.
A frequent disadvantage of known inhibitors of MMPs is the lack of specificity of the inhibition for only one class of MMPs. Most MMP inhibitors therefore inhibit a plurality of MMPs simultaneously.
In the endeavor to find effective compounds for the treatment of connective issue disorders, it has now been found that the compounds of the formula I are strong inhibitors of matrix metalloproteinases such as aggrecanase, for example ADAMTS-4, ADATMS-5 or ADAMTS-1 and tissue necoris factor α (TNF-α) converting enzyme.